Autophagy, amyloidogenesis and Alzheimer disease

Abstract

APP biology in briefAPP is a member of a family of conserved type 1 membrane proteins, which includes in mammals APP-like protein (APLP) 1 and APLP2 (Coulson et al., 2000;Senechal et al., 2006). Although its function remains uncertain, putative physiological roles in trafficking, neurotrophic signaling, cell adhesion and cell signaling have been proposed (Reinhard et al., 2005;Zheng and Koo, 2006;Hoareau et al., 2006).After APP is synthesized, the mature glycosylated form of APP in the trans-Golgi network (TGN) is delivered to the plasma membrane, where it is fairly rapidly turned over by either of two mechanisms (Fig. 3). An aspartyl protease at the cell surface, tumor necrosis factor ␣ converting enzyme Autophagy is the sole pathway for organelle turnover in cells and is a vital pathway for degrading normal and aggregated proteins, particularly under stress or injury conditions. Recent evidence has shown that the amyloid ␤ peptide is generated from amyloid ␤ precursor protein (APP) during autophagic turnover of APP-rich organelles supplied by both autophagy and endocytosis. A␤ generated during normal autophagy is subsequently degraded by lysosomes. Within neurons, autophagosomes and endosomes actively form in synapses and along neuritic processes but efficient clearance of these compartments requires their retrograde transport towards the neuronal cell body, where lysosomes are most concentrated. In Alzheimer disease, the maturation of autophagolysosomes and their retrograde transport are impeded, which leads to a massive accumulation of 'autophagy intermediates' (autophagic vacuoles) within large swellings along dystrophic and degenerating neurites. The combination of increased autophagy induction and defective clearance of A␤-generating autophagic vacuoles creates conditions favorable for A␤ accumulation in Alzheimer disease. Journal of Cell Science4083 Autophagy, amyloidogenesis and AD (TACE) or a distintegrin and metalloproteinase 10 (ADAM10) (Lopez-Perez et al., 2001;Buxbaum et al., 1998), also referred to as ␣-secretase, can mediate ␣-cleavage of APP within its lumenal/extracellular domain to generate a large soluble Nterminal fragment (sAPP␣), which is released from the cell, and a C-terminal fragment (CTF) that remains membrane associated. Alternatively, cell surface APP is internalized within early endosomes, where cleavage at a more distal site along the lumenal/extracellular domain by ␤-site-APPcleaving enzyme (BACE, ␤-secretase) releases a soluble APP fragment (sAPP ␤) and generates a membrane-associated 99-residue CTF (␤CTF) that contains the whole A␤ peptide. A transmembrane aspartyl protease that has optimal activity at low pH distributes predominantly to endosomes (Vassar et al., 1999;Capell et al., 2000;Walter et al., 2001), where ␤CTF has been shown to be generated (Grbovic, 2003;Mathews et al., 2002), although additional BACE is found in the TGN (von Arnim et al., 2006) (Fig. 3).A␤ is generated from ␤CTF by an intramembrane ␥-cleavage that yields predominantly a 40-mer peptide (A␤40) and s...

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“…S7). 36 In addition, patients with AD showed decreased IDE activity and levels in the CSF, and this reduction is correlated with cognitive impairment (Fig. 8).…”

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

“…In addition, there is evidence in AD that neuronal autophagy is induced but impaired at late steps in the pathway, which may help to explain the intracellular accumulation of Aβ and could contribute to its subsequent extracellular deposition in plaques. Accordingly, AD-causing mutations promote autophagy disruption in the autophagy-lysosomal pathway [80] . Microglial cells have also been found in senile plaques, suggesting that damage in the AD brain could derive from an autoimmune response of microglia that produces free radicals.…”

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

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